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Analysis of genetic variant associated with heart failure mortality implicates thymic stromal lymphopoietin as mediator of strain-induced myocardial fibroblast-mast cell crosstalk and fibrosis

Pimpalwar, Neha LU ; Celik, Selvi LU ; Karbalaei Sadegh, Mardjaneh LU ; Czuba, Tomasz LU ; Gidlöf, Olof LU and Smith, J. Gustav LU (2024) In FASEB Journal 38(4).
Abstract

Heart failure (HF) is a leading cause of death and disability globally. Heritable factors and the extent and pattern of myocardial fibrosis are important determinants of outcomes in patients with HF. In a genome-wide association study of mortality in HF, we recently identified a genetic polymorphism on chromosome 5q22 associated with HF mortality. Here, we sought to study the mechanisms by which this variant may influence myocardial disease processes. We find that the risk allele is located in an enhancer motif upstream of the TSLP gene (encoding thymic stromal lymphopoietin), conferring increased binding of the transcription factor nescient helix–loop helix 1 (NHLH1) and increased TSLP expression in human heart. Further, we find that... (More)

Heart failure (HF) is a leading cause of death and disability globally. Heritable factors and the extent and pattern of myocardial fibrosis are important determinants of outcomes in patients with HF. In a genome-wide association study of mortality in HF, we recently identified a genetic polymorphism on chromosome 5q22 associated with HF mortality. Here, we sought to study the mechanisms by which this variant may influence myocardial disease processes. We find that the risk allele is located in an enhancer motif upstream of the TSLP gene (encoding thymic stromal lymphopoietin), conferring increased binding of the transcription factor nescient helix–loop helix 1 (NHLH1) and increased TSLP expression in human heart. Further, we find that increased strain of primary human myocardial fibroblasts results in increased TSLP expression and that the TSLP receptor is expressed in myocardial mast cells in human single nuclei RNA sequence data. Finally, we show that TSLP overexpression induces increased transforming growth factor β expression in myocardial mast cells and tissue fibrosis. Collectively, our findings based on follow-up of a human genetic finding implicate a novel pathway in myocardial tissue homeostasis and remodeling.

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author
; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
cardiomyopathy, fibroblasts, fibrosis, heart failure, mast cells, tslp
in
FASEB Journal
volume
38
issue
4
article number
e23510
publisher
Wiley
external identifiers
  • pmid:38407489
  • scopus:85186390593
ISSN
0892-6638
DOI
10.1096/fj.202302000RR
language
English
LU publication?
yes
id
c94978e9-8026-486d-98fd-3e068b7f93a6
date added to LUP
2024-03-26 15:26:45
date last changed
2024-04-23 19:22:31
@article{c94978e9-8026-486d-98fd-3e068b7f93a6,
  abstract     = {{<p>Heart failure (HF) is a leading cause of death and disability globally. Heritable factors and the extent and pattern of myocardial fibrosis are important determinants of outcomes in patients with HF. In a genome-wide association study of mortality in HF, we recently identified a genetic polymorphism on chromosome 5q22 associated with HF mortality. Here, we sought to study the mechanisms by which this variant may influence myocardial disease processes. We find that the risk allele is located in an enhancer motif upstream of the TSLP gene (encoding thymic stromal lymphopoietin), conferring increased binding of the transcription factor nescient helix–loop helix 1 (NHLH1) and increased TSLP expression in human heart. Further, we find that increased strain of primary human myocardial fibroblasts results in increased TSLP expression and that the TSLP receptor is expressed in myocardial mast cells in human single nuclei RNA sequence data. Finally, we show that TSLP overexpression induces increased transforming growth factor β expression in myocardial mast cells and tissue fibrosis. Collectively, our findings based on follow-up of a human genetic finding implicate a novel pathway in myocardial tissue homeostasis and remodeling.</p>}},
  author       = {{Pimpalwar, Neha and Celik, Selvi and Karbalaei Sadegh, Mardjaneh and Czuba, Tomasz and Gidlöf, Olof and Smith, J. Gustav}},
  issn         = {{0892-6638}},
  keywords     = {{cardiomyopathy; fibroblasts; fibrosis; heart failure; mast cells; tslp}},
  language     = {{eng}},
  number       = {{4}},
  publisher    = {{Wiley}},
  series       = {{FASEB Journal}},
  title        = {{Analysis of genetic variant associated with heart failure mortality implicates thymic stromal lymphopoietin as mediator of strain-induced myocardial fibroblast-mast cell crosstalk and fibrosis}},
  url          = {{http://dx.doi.org/10.1096/fj.202302000RR}},
  doi          = {{10.1096/fj.202302000RR}},
  volume       = {{38}},
  year         = {{2024}},
}